The complex interrelationships of the receptors, neurotransmitters, and electrical impulses which affect the central nervous system are far from being fully understood. However, it has been possible to distinguish the effects of various pharmaceuticals and other drugs on aspects of the central nervous system that are exhibited as behaviors.
In particular, it is possible to distinguish an anxiolytic effect from a sedative one. Standard behavioral tests, such as the exploratory behavior test and the Vogel Conflict Paradigm described below can demonstrate and quantify the anxiolytic effects of various pharmaceutical agents. Other tests, including the prolongation of barbiturate-induced sleep time and the induction of sleep, show sedative and hypnotic effects, respectively.
While some agents are effective in inducing both anxiolysis and sedation, other agents, often structurally closely related, can be shown to exhibit primarily only one or the other activity. Moreover, the ability of useful antianxiety agents to exhibit primarily either anxiolytic or sedative activities is often related to dose (Wolff, M. E. (Ed.) Burger's Medicinal Chemistry, Part III, 4th ed. (1981) Wiley-Interscience, pp. 981-996; Foye, W. O. (Ed.) Principles of Medicinal Chemistry, 3rd ed. (1989) Lea and Febiger, pp. 143-237). Furthermore, there are additional demonstrable possible effects on the central nervous system such as the ability to induce or repress convulsions. Again, various structurally related compounds may or may not exhibit these abilities. What is clear from the art available at present is that there seem to be no clear structure-function correlations that can be made with respect to predicting the ability of a particular substance to affect or not affect the central nervous system in a prescribed manner.
The invention herein concerns the use of isovaleramide as a mild anxiolytic, and, at higher doses, as a mild sedative. It has been shown, as will be described hereinbelow, that these two effects of isovaleramide can be separated and emphasized based on dosage level.
FIG. 1 shows the structures of various known compounds which are structurally related to isovaleramide. In addition, as isovaleramide was initially prepared herein from extracts of the underground parts of Valeriana officinalis L. (common name: valerian) and extracts of this plant have been used historically as sedatives and antispasmodics, it is germane to indicate what is known about valerian extracts in this regard, as well as to discern the art concerning the compounds of FIG. 1.
The extracts of certain medicinal plants have been used for the reduction of stress and for the treatment of anxiety in many different cultures throughout the world since time immemorial, and a number of anxiolytic and sedative principles have been isolated from higher plants and characterized in modern times. Indeed, benzodiazepine tranquilizer compounds such as diazepam ("VALIUM"), oxazepam ("SERAX"), and lorazepam ("ATIVAN"), which have been considered to represent the quintessential synthetic anxiolytic agents par excellence, have now been shown unequivocally to be naturally occurring plant-derivable compounds, having been found in potatoes, soybeans, lentils, corn, wheat, buckwheat, rice, oats, barley, and millet (Wildmann et al., J. Neural Transm. (1987) 70:383-398; Wildmann, J. Biochem. Biophys. Res. Commun. (1988) 157:1436-1443; Wildmann et al., Biochem. Pharmacol. (1988) 37:3549-3559; Unseld et al., Biochem. Pharmacol. (1989) 38:2473-2478; Klotz, U., Life Sci. (1991) 48:209-215; Bringmann, G., J. Neural Transm. (1992) 88:77-82).
The use of valerian extracts for medicinal purposes has centuries of history behind it, but the active components have not been clearly or positively identified (Krieglstein, J. and D. Grusla, Deut. Apoth. Ztg. (1988) 128:2041-2046), nor has the nature of the effect of the extracts been clearly characterized and segregated into behaviorally distinguishable effects. The roots of valerian contain three principal classes of compounds: (a) the volatile oil(s), which are composed primarily of isovaleric acid and volatile monoterpenoid and sesquiterpenoid derivatives, (b) non-volatile monoterpenoid iridoids or valepotriates, and (c) monoterpenoid alkaloids. The monoterpenoid alkaloids are only minor components and are not considered to contribute significantly to the effects of valerian; similarly, the volatile oil fraction seems only weakly active. Attention has therefore focused on the valepotriate fraction, which is generally comprised of monoterpenoid (iridoid) esters. These esters are water insoluble, and cannot contribute entirely to the plant's sedative effect since aqueous extracts of valerian root exhibit sedative activity. The valepotriates may also be toxic (see below).
Recent studies on the valepotriates have shown that these compounds can irreversibly alkylate DNA and proteins and that small quantities of orally administered valepotriates actually reach the mouse brain and other organs intact (Wagner, H. and K. Jurcic, Planta Med. (1980) 38:366-376). However, in spite of this potentially hazardous toxicity, the valepotriate fractions have been marketed extensively as sedatives in Europe.
Ammoniated tinctures of valerian have also been used in the United States and Great Britain as sedatives, but only as crude mixtures.
The activities of chemically defined agents intended to affect the central nervous system show an interesting lack of pattern. Isovaleric acid, isovaleramide and related substances are known to elicit narcotic and hypnotic effects in experimental animals when administered in very high doses (Eeckhout, A. v. d., Arch. exptl. Pathol. Pharmakol. (1907) 57:338-357; Impens, E., Deut. med. Wochschr. (1912) 38:945-947; May, P., The Chemistry of Synthetic Drugs, 3rd ed. (1921) Longmans, Green and Co., p. 24; Meyer, K. H. and H. Hemmi, Biochem. Z. (1935) 277:39-71; Junkmann, K., Naunyn-Schmiedeberg's Arch. exptl. Pathol. Pharmakol. (1937) 186:552-564; Samson et al., J. Clin. Invest. (1956) 35:1291-1298; Teychenne et al., Clin. Sci. Molec. Med. (1976) 50(6):463-472). Furthermore, salts of isovaleric acid were used as sedatives in the early twentieth century, but it was considered that their effect was psychological and due to the stench of the highly volatile free acid (Hare et al., The National Standard Dispensatory (1905) Lea Brothers and Co., pp. 94, 159-160, 1619-1620; Grier, J., Chem. Drug. (1929) 110:420-422; Allport, N. L., The Chemistry and Pharmacy of Vegetable Drugs (1944) Chemical Publishing Co., pp. 159-161; Year Book of the American Pharmaceutical Association, 1912 (1914) 1: pp. 178-179; De Re Medicina (1938) Eli Lilly and Co., p. 159). Isovaleramide itself was shown to exhibit hypnotic activity only when administered to experimental animals in very high doses and was considered to be clinically useless as a hypnotic (Impens, E., Deut. med. Wochschr. (1912) 38:945-947; Junkmann, K., Naunyn-Schmiedeberg's Arch. exptl. Pathol. Pharmakol. (1937) 186:552-564). A series of .alpha.-brominated and/or .alpha.-alkylated isovaleramide derivatives, however, were considered successful in this regard (Volwiler, E. H. and D. L. Tabern, J. Am. Chem. Soc. (1936) 58:1352-1354; Burger, A., Medicinal Chemistry, Vol. 1, (1951) Interscience, pp. 131-132; Burger, A. (Ed.) Medicinal Chemistry, 2nd ed. (1960) Interscience, pp. 357-375; Burger, A. (Ed.), Medicinal Chemistry, Part II, 3rd ed. (1970) Wiley-Interscience, pp. 1365-1385; Wolff, M. E. (Ed.) Burger's Medicinal Chemistry, Part III, 4th ed. (1981) Wiley-Interscience, pp. 787-828).
Valnoctamide (see FIG. 1) is one such compound. Valnoctamide is a synthetic, barbiturate-derived, .alpha.-branched, water-insoluble compound which is purported to exhibit tranquilizing and anxiety-reducing properties which can quiet aggressive experimental animals and anxious humans (Stepansky, W., Curr. Therap. Res. (1960) 2:144-147; Goldberg, M., Dis. Nerv. Syst. (1961) 22:346-348; Roszkowski, A. P. and W. M. Govier, Int. J. Neuropharmacol. (1962) 1:423-430), and which produces hypnosis in rats at doses of 250 mg/kg IP. Although valnoctamide may appear superficially to be structurally similar to isovaleramide, there are considerable physicochemical and pharmacological differences between the two compounds. For example, valnoctamide is very water insoluble, while isovaleramide is essentially water soluble. Furthermore, valnoctamide exhibits pronounced hypnotic properties in rats at relatively low doses (e.g., 250 mg/kg [1.75 mM/kg]IP), whereas isovaleramide is not hypnotic in mice even in doses as high as 1000 mg/kg (9.90 mM/kg) IP, and exhibits hypnotic activity only at near-toxic dose levels (2000 mg/kg IP and higher). Thus, the pharmacological profile of valnoctamide appears to more closely resemble that of its synthetic barbiturate precursor than that of isovaleramide.
Valnoctamide contains two (chiral) stereocenters (the branched .alpha. and .beta. carbons); isovaleramide possesses no (chiral) stereocenters. Thus, "valnoctamide" is actually a mixed racemic preparation consisting of four stereoisomers in two diastereoisomeric sets of enantiomers. It is not known whether all four of these stereoisomeric forms are pharmacologically equivalent. We have demonstrated (by means of carbon-13 nuclear magnetic resonance [.sup.13 C-NMR] spectroscopy) that these two diastereomeric sets of enantiomers exist in unequal amounts in "valnoctamide". Since isovaleramide possesses no optically active (chiral) stereocenters, it exists as a single, clearly definable molecular entity with no alternative enantio- or diastereoisomeric forms, and its experimentally determined pharmacological properties and profile are those of a single, pure molecular entity.
Doses of isovaleramide as relatively low as 30-100 mg/kg IP in mice exhibit quantifiable CNS-depressant effects. Since the LD.sub.50 value of isovaleramide is greater than 4000 mg/kg IP in mice, the therapeutic index of the compound appears to be on the order of 40. A comparable value for valnoctamide is on the order of 11.4 (Roszkowski, A. P. and W. M. Govier, Int. J. Neuropharmacol. (1962) 1:423-430). Since valnoctamide is a barbiturate-derived compound, it shares some of the undesirable (in this case) properties of certain barbiturates, such as true hypnotic potential.
In addition, certain .alpha.-branched isovaleramide derivatives which are very closely structurally related to valnoctamide have been shown to exhibit a potential for producing hepatic porphyria (see, for example, Schmid, R. and S. Schwartz, Proc. Soc. Exptl. Biol. Med. (1952) 81:685-689; Case et al., Proc. Soc. Exptl. Biol. Med. (1953) 83:566-568; Goldberg, A., Biochem. J. (1954) 57(1):ii; Goldberg et al., Proc. Roy. Soc., Ser. B. (Biol. Sci.) (1955) 143:257-280; Talman et al., J. Biol. Chem. (1955) 212:663-675; Talman et al., Arch. Biochem. Biophys. (1957) 66:289-300; Goldberg, A. and C. Rimington, Diseases of Porphyrin Metabolism (1962) Charles C. Thomas, pp. 175-199; Granick, S., Ann. N. Y. Acad. Sci. (1965) 123:188-197; Marks et al., Biochem. Pharmacol. (1965) 14(7):1077-1084; de Barreiro, O. C., Biochem. Pharmacol. (1965) 14:1694-1696; Hirsch et al., Biochem. Pharmacol. (1966) 15(7):1006-1008; Hirsch et al. Biochem. Pharmacol. (1967) 16(8):1455-1462; Schneck et al., Biochem. Pharmacol. (1968) 17(7):1385-1399; Schneck, D. W. and G. S. Marks, Biochem. Pharmacol. (1972) 21(18):2509-2518), also a property shared in common with certain barbiturates, while isovaleramide has no hepatic porphyria-inducing properties, presumably because of a lack of steric hindrance at the .alpha. position to ready amide hydrolysis by liver enzymes (Hirsch et al., Biochem. Pharmacol. (1966) 15(7):1006-1008; Hirsch et al. Biochem. Pharmacol. (1967) 16(8):1455-1462; Schneck, et al., Biochem. Pharmacol. (1968) 17(7):1385-1399; Schneck, D. W. and G. S. Marks, Biochem. Pharmacol. (1972) 21(18):2509-2518).
Neodorm (see FIG. 1) has also been marketed as a sedative-hypnotic agent (Year Book of the American Pharmaceutical Association, 1929 (1931) 18:154); Year Book of the American Pharmaceutical Association, 1931 and 1932 (1934) 20,21:154). Several reports erroneously identify Neodorm as .alpha.-ethyl isovaleramide; however, it is known that the .alpha.-brominated structure shown in FIG. 1 is in fact the correct structure.
Derivatization (N-alkylation) of the nitrogen atom of the amide group has produced compounds such as N,N-diethylisovaleramide (A. Liebrecht, German Patent 129,967, issued 1902) which has been marketed as a sedative. However, this compound is shown hereinbelow to exhibit CNS-stimulating, anxiogenic, and convulsant properties. Indeed, N-methylated amide derivatives can show either CNS-stimulating or -depressing properties, whereas N-ethyl and larger derivatives generally possess CNS-stimulating properties (Volwiler, E. H. and D. L. Tabern, J. Am. Chem. Soc. (1936) 58:1352-1354; Nelson et al., J. Am. Pharm. Assoc., Sci. Ed. (1941) 30:180-182). This is analogous to the effect of addition or subtraction of methyl or methylene groups in other CNS agents such as catecholamine- and serotonin-like agents (F. W. Schueler (Ed.) Molecular Modification in Drug Design, Advances in Chemistry Series No. 45 (1964) American Chemical Society, pp. 114-139), the barbiturates (Burger, A. (Ed.) Medicinal Chemistry, Part II, 3rd ed. (1970) Wiley-Interscience, pp. 1365-1385), and other compound classes (Slater et al., J. Pharmacol. Exptl. Therap. ( 1954) 111:182-196), which can then exhibit either CNS-depressing or -stimulating properties.
Additional related compounds, valproic acid and valpromide (see FIG. 1) have been used as antiepileptic (anticonvulsant) drugs (Gilman et al. (Eds.) Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. (1990) Pergamon Press, pp. 436-462). However, isovaleramide itself has no anticonvulsant properties.
Thus, it is readily seen that there are no clearly discernible structure-function relationships which permit predictability of compounds which will affect the central nervous system in the experimentally distinguishable outcomes described hereinbelow. The finding that isovaleramide can be a useful mild anxiolytic agent and mild sedative at prescribed doses makes it a useful addition to the repertoire of available psychotherapeutic agents.